Molecular Psychiatry (2020) 25:3178–3185

https://doi.org/10.1038/s41380-020-0748-y

REVIEW ARTICLE

Autism spectrum heterogeneity: fact or artifact?

1
Laurent Mottron ●
Danilo Bzdok2,3

Received: 6 February 2020 / Revised: 11 April 2020 / Accepted: 20 April 2020 / Published online: 30 April 2020
© The Author(s) 2020. This article is published with open access

Abstract
The current diagnostic practices are linked to a 20-fold increase in the reported prevalence of ASD over the last 30 years.
Fragmenting the autism phenotype into dimensional “autistic traits” results in the alleged recognition of autism-like
symptoms in any psychiatric or neurodevelopemental condition and in individuals decreasingly distant from the typical
population, and prematurely dismisses the relevance of a diagnostic threshold. Non-specific socio-communicative and
repetitive DSM 5 criteria, combined with four quantitative specifiers as well as all their possible combinations, render
limitless variety of presentations consistent with the categorical diagnosis of ASD. We propose several remedies to this
problem: maintain a line of research on prototypical autism; limit the heterogeneity compatible with a categorical diagnosis
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to situations with a phenotypic overlap and a validated etiological link with prototypical autism; reintroduce the qualitative
properties of autism presentations and of current dimensional specifiers, language, intelligence, comorbidity, and severity in
the criteria used to diagnose autism in replacement of quantitative “social” and “repetitive” criteria; use these qualitative
features combined with the clinical intuition of experts and machine-learning algorithms to differentiate coherent subgroups
in today’s autism spectrum; study these subgroups separately, and then compare them; and question the autistic nature of
“autistic traits”

Introduction
The heterogeneity of autism is now universally accepted, at
the phenotypic level under the DSM-5 term “spectrum”, as
well as at the imaged brain [1] and etiology [2] levels. The
overarching pervasive developmental disorders (PDD) cate-
gory of the DSM-IV initiated a deviation towards less pro-
totypical presentations of autism. Asperger’s syndrome was
considered to be autism without the requirement of language
signs and PDD not otherwise specified as subthreshold autism
of various types. The current DSM-5 definition of autism
spectrum disorder (ASD) merged the PDD subgroups inter
alia, due to their poor inter-judge reliability and instability
* Laurent Mottron
Laurent.mottron@gmail.com
1
Department of Psychiatry, University of Montreal and Researcher
for the CIUSSS-NIM, Rivière-des-Prairies Hospital, 7070, Perras
Boul, Montreal, QC H1E 1A4, Canada
2 ning of intervention and educational services. What is
Department of Biomedical Engineering, McConnell Brain
Imaging Centre, Montreal Neurological Institute, Faculty of
Medicine, McGill University, Montreal, QC H3A 2B4, Canada
3
Mila - Quebec Artificial Intelligence Institute, Montreal, QC H2S
3H1, Canada
over time [3]. Doing away with PDD not otherwise specified
as a category, which was responsible for the considerable
increase of reported prevalence at the time, but for which the
criteria were insufficiently reliable, [4] was expected to
increase the specificity of the categorical diagnosis [5].
The evolution of the DSM has been accompanied by a
20-fold increase in the reported prevalence of ASD over the
last 30 years, reaching a current prevalence of more than 2%
in the United States [6] (Fig. 1a). The implementation of
standardized retrospective [7] and observational diagnostic
tools [8] in the diagnostic process has not limited this trend
and may have even contributed to it in the clinical setting,
possibly due to their lack of specificity towards other
childhood psychiatric conditions [9] and the false sense of
security they provide when someone “meets diagnostic
criteria [10]”, despite clinical inconsistency with proto-
typical presentations.
A single categorical diagnosis, which encompasses such
heterogeneity of developmental history, intelligence,
comorbidity, and severity, poorly contributes to the plan-
common between intervention strategies supporting an adult
with academic-level written and oral language and an
intellectually disabled, syndromic autistic child with major
self-injurious behaviors [11]?
Autism spectrum heterogeneity: fact or artifact?
Fig. 1 Temporal trends in autism research. a The change in autism
prevalence over time, based on data from [65–67]. Methodologies may
differ between studies. b The changes in group-level standardized
mean differences between autism and control samples over time, as
described by Rødgaard et al. (2019) [14]. A significant downwards
temporal trend was observed in five of seven investigated constructs in
In addition to the clinical consequences, these considera-
tions also have important ramifications for conducting and
interpreting research studies. Currently, the modest state of
genetic [12] knowledge of non-syndromic autism and the
polygenic heterogeneity across ASD subtypes [13] suggests
that we may need to update our research targets and strategies.
The effect sizes obtained from cognitive, EEG, and neuro-
anatomical studies of autism decreased by up to 80% between
2000 and 2015 [14] (Fig. 1b), even when accounting for
sample size and quality. The cause of this trend is yet to be
determined but likely includes a reduction in the deviation
from the norm required to reach the threshold for a categorical
diagnosis [15], and the poor specificity of current diagnostic
criteria for extreme values of age, intelligence, and severity
[16]. Other important factors that may contribute to this trend
include the disappearance of differential exclusion diagnoses,
as well as the absence of an “economy principle”, privileging
the diagnosis which best explains the presented symptoms
[17]. The presence of such “self-inflicted” heterogeneity
plausibly distorts the autistic signal and negatively influences
the ability to make replicable discoveries.
3179
autism. c The number of published studies investigating autistic traits
in the normal population and for other clinical conditions, showing an
eightfold increase during the last decade. d The number of published
empirical studies performing research on autism, showing a fourfold
increase during the last decade. (“c”,“d” source: Pubmed).
The wide-ranging disappearance of studies on differ-
ential diagnosis contrasts with the explosion of meta-
analyses and systematic reviews (respectively less than 1/
1000 vs. 3% of the autism literature in 2019). Most scien-
tific knowledge of autism is obtained through condensing
findings on an increasingly heterogeneous and decreasingly
atypical population, without questioning the case ascer-
tainment on which this knowledge is grounded. All research
is carried out downstream of diagnostic criteria, little of it
upstream. Sociologically, we are living in a time of reba-
lancing the traditional emphasis on stringent inclusion and
exclusion criteria for clinical neuroscience studies. There
is also growing interest in deriving insight from population
and prospective cohorts with thousands of subjects [18]. As
a necessary side effect of these developments in research
trends, many autism-vs.-non-autism classification studies
have become difficult to reproduce in these heterogeneous
cohorts of unprecedented breadth [19]. We thus highlight
the dilemma between the high predictive accuracies of
preselected samples and much lower predictive accuracies
of more naturally acquired subject samples [20]. In this
3180
context, the co-existence of qualitative and quantitative
autism traits may have critical consequences for the future
of single-patient predictions in precision psychiatry.
Confronting essentialist and nominalist
views of autism
We are still uncertain about the entity of autism. It can
either appear to have a natural basis (“essentialist” position)
or as multi-determinant, for which unity is in the eye of the
viewer or the vocabulary they use (“nominalist” position).
Although we are able to recognize this clinical condition
with good reliability, we are not yet very skilled at defining
it in a specific way. We also know that the signs that
characterize it are not always simultaneously present, and/or
that they can appear to be attenuated, making delineation of
the autism category difficult.
However, the two positions should still compete for the
truth. The absence of a categorical limit and the multiplicity of
aetiologies and risk factors reported previously [21–23]
anticipate the current state of knowledge. To be able to
determine whether autism has a natural basis or not, the two
positions should be given equal weight, as the validity of
either is still undecidable in the current state of autism diag-
nosis. This requires studying individuals who are very similar
to each other to obtain biomarkers, then to search for these
markers in attenuated phenotypes. This does not guarantee
that we will find a single basis in primary biology. However,
if we start from the spectrum as currently defined, it is clear
that we will not find this single cause, if it exists.
DSM-5 criteria for autism may produce
spurious heterogeneity
Combining nonspecific social and repetitive categorical
criteria with four “open” specifiers (levels of intelligence,
language, severity, and comorbidity), as well as all their
possible combinations, can result in a vast array of ASD
presentations. However, does such variability truthfully
reflect diversity in cognition, the brain, and genes?
The quantitative nature and poor specificity of signs
which, when combined, result in a categorical
diagnosis
The categorical diagnosis of ASD is currently obtained by
pass/fail scoring of seven signs (i.e., three social and four
repetitive), mostly quantitative (e.g., less socially-oriented
behaviors), rather than qualitative (those that can be
recognized). These signs are inherently imprecise due to
their quantitative/dimensional nature (how do we define a
L. Mottron, D. Bzdok
threshold for “lack of socialization?”) and open character
(from… to….), leading to the bundling of a variety of
phenotypes that are not specific to autism. For example,
autistic gaze atypicality and an embarrassed look are qua-
litatively distinct, but both make it possible to positively
score the A2 criterion, “Deficits in nonverbal commu-
nicative behaviors used for social interaction”. Conversely,
a rapid initial gaze at faces, followed by the apparent
absence of behavioral hallmarks for social reciprocity,
would become more specific by the addition of qualitative
dimensions [24]. Certain signs (B2, “rigidity”, and B4,
“sensory”), which when associated allow one to reach the
diagnostic threshold in the area of repetitive behaviors, are
also observed in a large proportion of children with other
neurodevelopmental and psychiatric disorders [25, 26].
Indeterminate nature of the clinical specifiers
The four clinical specifiers of ASD were originally designed
to account for the unavoidable heterogeneity of autistic pre-
sentation, for example, between nonverbal and hyper-verbal
individuals, while preserving the category. These specifiers
now exacerbate the heterogeneity of the individuals included
in this spectrum, transforming the autism diagnosis into a
category as vague as “intellectual disability” and “neurode-
velopmental disorders”. A common characteristic of the four
clinical specifiers is their dimensional, quantitative, and
clinically nonspecific nature. Moreover, there are no con-
straints on how the qualitative properties of the seven criteria
are modified according to the expression of each of the spe-
cifiers, which misses a major opportunity to increase speci-
ficity. For example, a dissociation between advanced
knowledge of letters and numbers and poor pragmatic use of
verbs would contribute qualitative information to a quantita-
tive ‘’language” specifier [27].
Conceptual ambiguity favors heterogeneity
Two conceptual sources of imprecision may further con-
tribute to the current heterogeneity of the autism spectrum:
the belief that the clinical threshold for autism is necessarily
arbitrary, and the acceptance of any identified neurogenetic
or psychiatric condition as a comorbidity, combined with
the absence of exclusion criteria or recommended differ-
ential diagnoses.
Is the clinical threshold arbitrary?
A major additional source of heterogeneity in the ASD
spectrum is the lowering of the threshold for clinical sig-
nificance required for the inclusion of individuals who are
less different from typical individuals [15]. This escalation in
Autism spectrum heterogeneity: fact or artifact?
flexibility is frequently justified by the consensus in autism
research that clinical thresholds are necessarily arbitrary and/
or do not reach reliability among clinicians. The corre-
sponding justification is typically grounded on the philoso-
phical tradition of questioning the status of “natural”
boundaries [28]. The description of natural categories
separated by objective boundaries has been, since Plato’s
illuminating metaphor, compared with “carving nature at its
joints”: a butcher does not question the natural boundaries of
joints when preparing meat. In defense of the hypothetically
arbitrary nature of autism boundaries, this analogy has been
ironically transformed by likening the search for a catego-
rical boundary for autism into “carving meatloaf at its joint
[29]”. These “joints” were however visible when autism was
initially discovered decades ago. However, they disappeared
as an effect of the “grinding” of autistic phenotypes into
symptoms or traits. The replacement of pattern-like recog-
nition with the use of polythetic criteria in an effort to make
such clinical recognition a reliable and objective process has
failed. Heterogeneity has introduced itself into the spaces
between clinical sub-prototypes and has been authorized by
their common inclusion in an overarching, criteria-based
category. Hence, the meatloaf “spectrum”.
Syndromic vs. non-syndromic autism
Although the reported increase in prevalence of autism-
like syndrome in a limited number of identifiable neuro-
genetic syndrome (e.g., Fragile X, Williams syndrome) or
identified copy-number variations (e.g., 16p11.2) is
recognized, it has also been demonstrated that any neu-
rodevelopmental condition accompanied by a certain
degree of intellectual disability and behavioral issues
increases the probability of satisfying certain autism cri-
teria [30]. The syndromic/non-syndromic distinction has
been questioned by some on the basis that today’s non-
syndromic autistic presentations will be tomorrow’s syn-
dromic ones, following new discoveries. Waiting for this
promised land, the bundling of non-syndromic and syn-
dromic autism assumes external validity for the
entire spectrum of discoveries made in patients and
animal models with an identified condition sometimes
comorbid with autism-like presentations. However, this
contention is not supported by the phenotypic dissim-
ilarity between autism with and without penetrant
de novo genetic variants [31], nor by the mechanistic
differences between the strong effects of reliably identi-
fied de novo mutations, on the one hand, and the additive
weak effects associated with common variants [13, 32],
on the other. In addition, the multiple mutations and
pathogenic pathways associated with syndromic autism
are only rarely/exceptionnaly [33] traced in non-
syndromic autism.
3181
Are “autistic traits” autistic?
The concept of an autistic trait and the demonstration that
“autistic traits are continuously distributed throughout the
general population [34]” through instruments such as the
Autism Screening Questionnaire [35] and Social Respon-
siveness Scale [36] has led to the flowering of multiple studies
associating autistic traits with nonmedical conditions (e.g.,
masculinity) [37], separate diagnoses (e.g., anorexia) [38], or
in people exposed to a myriad of supposed etiological factors
(e.g., cesarean birth) [39]. The increase in the number of such
studies during the last decade has been twice as large as for
the total number of empirical studies of autism (Fig. 1c,d).
Studies reporting autistic traits in a large number of psy-
chiatric or neurological conditions consider them by default as
autistic traits rather than socialization features associated with
a particular, non-autistic condition. Are these “autistic traits”
themselves autistic? The answer is “no” if they are extracted
from the pattern they compose in combination with other
traits. All striped animals are not tigers, and all stripes are not
tiger stripes.
Disentangling potentially artifactual from
genuine heterogeneity
There is, however, heterogeneity that plausibly belongs to
the autism signal when the kinship between a prototypical
clinical presentation and an altered version is biologically
validated. Examples of this include developmental trans-
formations, some (but not all) variations in presentation
according to intelligence and language level, and the
familial aggregation of autism subtypes.
Developmental transformation
Removing variation due to age by a de-confounding
procedure that integrates the time course in the sign
characteristic is likely to remove at least part of the het-
erogeneity introduced by one of the dominant sources of
population variation [40]. However, the developmental
transformation of autistic signs [41], while generally
trending towards a smaller difference from typicality with
age [42], is not a continuous process. Numerous signs in
the area of repetitive behaviors and restricted interests
present their own developmental course [43], such as, for
example, “hand leading”, which is used by a child to
nonverbally indicate what he wants. It therefore combines
an atypical manner of requesting (positive for the
“abnormal social approach” sign) with a specific
language-specifier value (speechless plateau), nonverbal
intelligence (in the normal range), and a certain age range
(2–5 years). Similarly, hand flapping, lateral glances, the
3182
absence of overt joint attention, and even most self-
injurious behaviors have a “golden age”. These con-
siderations would justify the coupling of age of occur-
rence with specifier values, and qualitatively defined
categorical signs, which could increase the capacity of the
clinician to recognize an autistic feature.
Does familial aggregation of autism subtypes and
other psychiatric diagnoses validate autism
heterogeneity?
Studies of first-degree relatives of autistic people demon-
strate an increased prevalence of cognitive, motor, and
psychiatric differences relative to the general population
[44]. Familial aggregation of multiple presentations
encompassed under the autism spectrum category range
from discrepant autism subtypes (e.g., with and with-
out Speech Onset Delay (SOD) [45]) in siblings to sub-
threshold atypicalities or a “broader autism phenotype”. At
its most extreme, there is a familial co-occurrence of con-
ditions which minimally overlap with the autism phenotype
and are clinically considered as differential diagnoses at the
phenotypic level, such as specific language impairment
[46], or as an unambiguously different type, such as mood
disorders [47].
Such familial aggregation validates a certain mechanistic
relationship between a prototypical and less prototypical
presentation of autism. However, it should not result in
encompassing any presentation with a trivial resemblance to
autism under a “subthreshold” or “trait” dimension. The
independence between genetic alterations and the resulting
phenotype associated with them is a well-accepted trivial
finding in behavioral genetics. For example, the 22q11.2
deletion syndrome shows variable penetrance and is asso-
ciated with multiple, phenotypically unrelated psychiatric
presentations [48]. In contrast, a minimal variation of the
dominant social phenotype in any condition or in the typical
population can still be labeled “autistic” [34], even
in situations in which the relationship with the full-blown
phenotype is unproven—another example of an unfounded
“autism exception”.
Acknowledging the effect of artifactual
heterogeneity in clinical settings and
research programs
The decrease in effect-sizes in neurocognitive autism
research over time is likely due to increased artifactual
heterogeneity, which affects our ability to construct neuro-
biological models of autism. We propose that these pro-
blems may be mitigated by modifying the diagnostic criteria
and prevalent research strategies.
L. Mottron, D. Bzdok
Re-building autism subgroups from the recognition
of its most prototypical forms
There is more information in the brains of autism experts
than that provided by diagnostic instruments. Thus, new
criteria should be built from such expertize by decomposing
the phenotype of a prototypical population into the quali-
tative signs that contribute to recognizing autism, which do
not coincide with the DSM signs. Experts recognize more
reliably “frank” autism than any of the diagnostic instru-
ments developed to operationalize this diagnosis using
check-list criteria [49]. Importantly, this reliability was
independent of age, IQ, and level of functioning. The top-
down search for behaviors corresponding to criteria during a
diagnostic process is intrinsically more inclusive that the
bottom-up recognition of the behavioral patterns that such
criteria are based on. Any forthcoming revision of the
diagnostic criteria for autism should also restrict the current
number of combinatorial possibilities of the clinical speci-
fiers. Instead, it may be beneficial to associate specific
combinations of values of these specifiers with specific
clinical subtypes.
Study autism subgroups separately, then compare
them
Instead of an a priori assumption that all presentations of
ASD represent the same condition, it would be beneficial to
study potential autism subgroups separately and merge
them only if they are similar for targeted variables. Beyond
non-syndromic autism with and without SOD, candidate
subgroups include syndromic autism, and validated and
non-validated subthreshold individuals. Excluding the
aspect of speech from the diagnostic criteria accounts for
much heterogeneity and increases the risk of losing the
information conveyed by speech to the diagnosis. Having or
not a history of SOD has a lifelong impact, not only on
language and speech [50] but also on the nature of peaks of
abilities [51], intelligence subtest profiles [52], motor dif-
ficulties [53], domains of interest [54], lateralization of brain
structures [55] and functions [56], gyrification [57], white
matter [58], and neural activity during speech-like proces-
sing [59], which are unavoidably blurred when the two
subgroups are analyzed together.
Other possible combinations of IQs, co-occurring con-
ditions, and speech levels or histories may also define
relevant subgroups, each with its own neurological and
genetic correlates and co-existing symptoms. The absence
of such precaution results in the dilution of biological or
neurocognitive markers, which are only evident in proto-
typical individuals, representing the center of a category or
subcategory. This dilution biases meta-analyses in favor of
type 2 errors [60], closing avenues opened in the first years
Autism spectrum heterogeneity: fact or artifact?
of autism research [61]. The assumption that co-variation of
specifier values in the target analyses will separate their role
in the variables under study is only tenable “everything else
being equal”, which is wrong if studies inadvertently col-
lapse differently heterogeneous subgroups, known as
Simpson’s paradox [62].
Research autism before the autism spectrum
Conserving a distinct line of research dedicated to proto-
typical autism is still justified, whereas it is at risk of dis-
appearing under the current spectrum approach to diagnosis.
For example, studying the gradual improvement of socio-
communicative signs between preschool and school age in
children with an initial prototypical presentation provides
information on the temporal characteristics of these signs
[63]. Such knowledge would help improve the specificity of
these signs and their contribution to retrospective diagnoses.
It is also necessary to preserve a threshold of qualitative
similarity with the prototypical autism phenotype, in addi-
tion to the non-specific severity threshold.
Re-conceptualize autistic signs/traits
The relationship, either mechanistic or phenotypic, between
“autistic traits” and autism, implied by the use of the term
“autistic” trait rather than “social” or “repetitive” trait,
should be scientifically validated, despite some potentially
superficial resemblance. Their “autistic” quality should be
ascertained by a) their qualitative aspects, b) their co-
occurrence in the prototypical condition, and c) their con-
textual validation, as the demonstration of a previous,
developmentally anterior, above-threshold presentation.
Trait studies in the general population or certain non-autistic
conditions are not informative about above-threshold autism
unless the trait-autism link is validated, revealing the weak
overlap between genetic proximity and phenotypic simi-
larity [64]. Until there is such validation, “autistic traits” are
not yet “autistic”. The very notion of “autistic traits”, as in
“are there autistic traits in the condition X” may be flawed
outside of a context in which their autistic nature is
validated.
Conclusion
The widely acknowledged heterogeneity of the autism
spectrum is not a biological fact of nature. Neither does it
have the force of a scientific fact resulting from empirically
and logically sound research. Our current notion of autism
is partly a result of our ignorance, reinforced by non-
specific criteria and the longing for a consensus. The dis-
appearance of the differential diagnosis of autism as a
3183
research question, the unfounded but consensual assimila-
tion of autism and autistic traits, and meta-analyses that
condense results contaminated by premature assumptions
into apparent truth all promote a lasting mechanism to
produce null findings. The time has come to usher research
on autism towards prototypical individuals and to limit the
heterogeneity of autism to a situation in which the variants
of the autism phenotype have a traceable link with proto-
typical autistic individuals.
Acknowledgements We thank Julie Bareil, Stéphanie Caillé, Alexis
Beauchamp-Chatel, Daniel Chicouene, Michelle Dawson, Nada
Esseily, Melissa Faivre, Baudoin Forgeot d’Arc, David Gagnon, Catie-
anne Gagnon, Pascale Grégoire, Guillaume Huguet, Drigissa Ilies,
François Lesperance, Sebastien Jacquemont, Edith Ménard, Azalée
Mongrain-McNally, Soizic Peignot, Juliette Rabot, and Eya-Mist
Rødgaard for the exchanges of ideas that took place during the
development of this article.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
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References
1. Martinez-Murcia FJ, Lai MC, Górriz JM, Ramírez J, Young AM,
Deoni SC, et al. On the brain structure heterogeneity of autism:
Parsing out acquisition site effects with significance-weighted prin-
cipal component analysis. Hum Brain Mapp. 2017;38:1208–23.
2. Jeste SS, Geschwind DH. Disentangling the heterogeneity of
autism spectrum disorder through genetic findings. Nat Rev
Neurol. 2014;10:74–81.
3. Lord C, Bishop SL. Recent advances in autism research as
reflected in DSM-5 criteria for autism spectrum disorder. Annu
Rev Clin Psychol. 2015;11:53–70.
4. Mandy W, Charman T, Gilmour J, Skuse D. Toward specifying
pervasive developmental disorder-not otherwise specified. Autism
Res. 2011;4:121–31.
5. Wiggins LD, Rice CE, Barger B, Soke GN, Lee LC, Moody E,
et al. DSM-5 criteria for autism spectrum disorder maximizes
diagnostic sensitivity and specificity in preschool children. Soc
Psychiatry Psychiatr Epidemiol. 2019;54:693–701.
3184
6. Kogan MD, Vladutiu CJ, Schieve LA, Ghandour RM, Blumberg
SJ, Zablotsky B et al. The prevalence of parent-reported autism
spectrum disorder among US children. Pediatrics 2018;142.
7. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-
Revised (ADI-R): a revised version of a diagnostic interview for
caregivers of individuals with possible pervasive developmental
disorders. Western Psychol. Services 1994.
8. Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood
L, et al. Autism diagnostic observation schedule (ADOS-G): a
standardized observation of communicative and social behavior. J
Autism Dev Disord. 1989;19:185–212. 1989/06/01 ednpp
9. Molloy CA, Murray DS, Akers R, Mitchell T, Manning-Courtney
P. Use of the autism diagnostic observation schedule (ADOS) in a
clinical setting. Autism. 2011;15:143–62.
10. Fombonne E. Editorial: the rising prevalence of autism. J Child
Psychol Psychiatry. 2018;59:717–20.
11. Green J. Editorial Perspective: delivering autism intervention
through development. J Child Psychol Psychiatry. 2019;60:1353–6.
12. Sestan N, State MW. Lost in translation: traversing the complex
path from genomics to therapeutics in autism spectrum disorder.
Neuron. 2018;100:406–23.
13. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H,
et al. Identification of common genetic risk variants for autism
spectrum disorder. Nat Genet. 2019;51:431–44.
14. Rødgaard EM, Jensen K, Vergnes JN, Soulières I, Mottron L.
Temporal changes in effect sizes of studies comparing individuals
with and without autism: a meta-analysis. JAMA Psychiatry.
2019;76:1124–32.
15. Arvidsson O, Gillberg C, Lichtenstein P, Lundström S. Secular
changes in the symptom level of clinically diagnosed autism. J
Child Psychol Psychiatry. 2018;59:744–51.
16. Thurm A, Farmer C, Salzman E, Lord C, Bishop S. State of the
field: differentiating intellectual disability from autism spectrum
disorder. Front Psychiatry. 2019;10:526.
17. First MB. Mutually exclusive versus co-occurring diagnostic
categories: the challenge of diagnostic comorbidity. Psycho-
pathology. 2005;38:206–10.
18. Bzdok D, Nichols TE, Smith SM. Towards algorithmic analytics
for large-scale datasets. Nat Mach Intell. 2019;1:296–306.
19. Woo CW, Chang LJ, Lindquist MA, Wager TD. Building better
biomarkers: brain models in translational neuroimaging. Nat
Neurosci. 2017;20:365–77.
20. Bzdok D, Meyer-Lindenberg A. Machine learning for precision
psychiatry: opportunities and challenges. Biol Psychiatry Cogn
Neurosci Neuroimaging. 2018;3:223–30.
21. Happe F, Frith U. Annual Research Review: Looking back to look
forward - changes in the concept of autism and implications for
future research. J Child Psychol Psychiatry. 2020;61:218–32.
22. Elsabbagh M. Linking risk factors and outcomes in autism spectrum
disorder: is there evidence for resilience? BMJ. 2020;368:l6880.
23. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. Autism
spectrum disorder. Lancet. 2018;392:508–20.
24. Schauder KB, Park WJ, Tsank Y, Eckstein MP, Tadin D, Ben-
netto L. Initial eye gaze to faces and its functional consequence on
face identification abilities in autism spectrum disorder. J Neuro-
dev Disord. 2019;11:42.
25. Fuermaier ABM, Hupen P, De Vries SM, Muller M, Kok FM,
Koerts J, et al. Perception in attention deficit hyperactivity dis-
order. Atten Defic Hyperact Disord. 2018;10:21–47.
26. Lange F, Seer C, Muller-Vahl K, Kopp B. Cognitive flexibility
and its electrophysiological correlates in Gilles de la Tourette
syndrome. Dev Cogn Neurosci. 2017;27:78–90.
27. Ostrolenk A, Forgeot d’Arc B, Jelenic P, Samson F, Mottron L.
Hyperlexia: systematic review, neurocognitive modelling, and
outcome. Neurosci Biobehav Rev. 2017;79:134–49.
L. Mottron, D. Bzdok
28. Varzi A. Boundary. In: Zalta EN, editors. The Stanford Ency-
clopedia of Philosophy (Winter 2015). Stanford: The Metaphysics
Research Lab; 2015.
29. Happe F. Criteria, categories, and continua: autism and related
disorders in DSM-5. J Am Acad Child Adolesc Psychiatry.
2011;50:540–2.
30. Havdahl KA, Hus Bal V, Huerta M, Pickles A, Øyen AS, Stol-
tenberg C, et al. Multidimensional influences on autism symptom
measures: implications for use in etiological research. J Am Acad
Child Adolesc Psychiatry. 2016;55:1054–1063.e1053.
31. Bishop SL, Farmer C, Bal V, Robinson EB, Willsey AJ, Werling
DM, et al. Identification of developmental and behavioral markers
associated with genetic abnormalities in autism spectrum disorder.
Am J Psychiatry. 2017;174:576–85.
32. Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA,
Grove J, et al. Polygenic transmission disequilibrium confirms that
common and rare variation act additively to create risk for autism
spectrum disorders. Nat Genet. 2017;49:978–85.
33. Baudouin SJ, Gaudias J, Gerharz S, Hatstatt L, Zhou K, Punnakkal
P, et al. Shared synaptic pathophysiology in syndromic and non-
syndromic rodent models of autism. Science. 2012;338:128–32.
34. Constantino JN. The quantitative nature of autistic social
impairment. Pediatr Res. 2011;69:55R–62R.
35. Berument SK, Rutter M, Lord C, Pickles A, Bailey A. Autism
screening questionnaire: diagnostic validity. Br J Psychiatry.
1999;175:444–51.
36. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM,
Brophy SL, et al. Validation of a brief quantitative measure of
autistic traits: comparison of the social responsiveness scale with
the autism diagnostic interview-revised. J Autism Dev Disord.
2003;33:427–33.
37. Greenberg DM, Warrier V, Allison C, Baron-Cohen S. Testing the
Empathizing-Systemizing theory of sex differences and the
Extreme Male Brain theory of autism in half a million people.
Proc Natl Acad Sci USA. 2018;115:12152–7.
38. Westwood H, Eisler I, Mandy W, Leppanen J, Treasure J,
Tchanturia K. Using the autism-spectrum quotient to measure
autistic traits in anorexia nervosa: a systematic review and meta-
analysis. J Autism Dev Disord. 2016;46:964–77.
39. Curran EA, O’Neill SM, Cryan JF, Kenny LC, Dinan TG, Kha-
shan AS, et al. Research review: Birth by caesarean section and
development of autism spectrum disorder and attention-deficit/
hyperactivity disorder: a systematic review and meta-analysis. J
Child Psychol Psychiatry. 2015;56:500–508.
40. Bzdok D, Floris D, Marquand A. Analyzing brain networks in
population neuroscience: a case for the Bayesian Philosophy.
Philos. Trans. Royal Society B In Press.
41. Georgiades S, Bishop SL, Frazier T. Editorial perspective: long-
itudinal research in autism - introducing the concept of ‘chron-
ogeneity’. J Child Psychol Psychiatry. 2017;58:634–636.
42. Fecteau S, Mottron L, Berthiaume C, Burack JA. Developmental
changes of autistic symptoms. Autism. 2003;7:255–268.
43. Mottron L, Mineau S, Martel G, Bernier CS, Berthiaume C,
Dawson M, et al. Lateral glances toward moving stimuli among
young children with autism: early regulation of locally oriented
perception? Dev Psychopathol. 2007;19:23–36.
44. Piven J, Wzorek M, Landa R, Lainhart J, Bolton P, Chase GA,
et al. Personality characteristics of the parents of autistic indivi-
duals. Psychol Med. 1994;24:783–795.
45. Szatmari P, Mérette C, Emond C, Zwaigenbaum L, Jones MB,
Maziade M, et al. Decomposing the autism phenotype into
familial dimensions. Am J Med Genet B Neuropsychiatr Genet.
2008;147B:3–9.
46. Marrus N, Hall LP, Paterson SJ, Elison JT, Wolff JJ, Swanson
MR, et al. Language delay aggregates in toddler siblings of
Autism spectrum heterogeneity: fact or artifact?
children with autism spectrum disorder. J Neurodev Disord.
2018;10:29.
47. Mazefsky CA, Folstein SE, Lainhart JE. Overrepresentation of
mood and anxiety disorders in adults with autism and their first-
degree relatives: what does it mean? Autism Res. 2008;1:193–197.
48. Biswas AB, Furniss F. Cognitive phenotype and psychiatric dis-
order in 22q11.2 deletion syndrome: A review. Res Dev Disabil.
2016;53-54:242–57.
49. De Marchena A, Miller J. “Frank” presentations as a novel
research construct and element of diagnostic decision-making in
autism spectrum disorder. Autism Res. 2016;653–62.
50. Barbeau E, Soulieres I, Dawson M, Zeffiro TA, Mottron L. The
level and nature of autistic intelligence III: Inspection time. J
Abnorm Psychol. 2013;122:295–301.
51. Bonnel A, McAdams S, Smith B, Berthiaume C, Bertone A,
Burack J, et al. Enhanced pure-tone pitch discrimination among
persons with autism but not Asperger syndrome. Neuropsycho-
logia. 2010;48:2465–75.
52. Soulières I, Dawson M, Gernsbacher MA, Mottron L. The level
and nature of autistic intelligence II: what about Asperger syn-
drome? PLoS ONE. 2011;6:e25372.
53. Barbeau EB, Meilleur AA, Zeffiro TA, Mottron L. Comparing
Motor Skills in Autism Spectrum Individuals With and Without
Speech Delay. Autism Res. 2015;8:682–93.
54. Chiodo L, Majerus S, Mottron L. Typical versus delayed speech
onset influences verbal reporting of autistic interests. Mol Autism.
2017;8:35.
55. Lai MC, Lombardo MV, Ecker C, Chakrabarti B, Suckling J,
Bullmore ET, et al. Neuroanatomy of individual differences in
language in adult males with autism. Cereb Cortex.
2015;25:3613–28.
56. Rinehart NJ, Bradshaw JL, Brereton AV, Tonge BJ. Lateralization
in individuals with high-functioning autism and Asperger’s disorder:
a frontostriatal model. J Autism Dev Disord. 2002;32:321–31.
57. Duret P, Samson F, Pinsard B, Barbeau EB, Boré A, Soulières I,
et al. Gyrification changes are related to cognitive strengths in
autism. Neuroimage Clin. 2018;20:415–23.
3185
58. McAlonan GM, Cheung C, Cheung V, Wong N, Suckling J, Chua
SE. Differential effects on white-matter systems in high-
functioning autism and Asperger’s syndrome. Psychol Med.
2009;39:1885–93.
59. Samson F, Zeffiro TA, Doyon J, Benali H, Mottron L. Speech
acquisition predicts regions of enhanced cortical response to
auditory stimulation in autism spectrum individuals. J Psychiatr
Res. 2015;68:285–92.
60. Van der Hallen R, Evers K, Brewaeys K, Van den Noortgate W,
Wagemans J. Global processing takes time: a meta-analysis on
local-global visual processing in ASD. Psychol Bull.
2015;141:549–73.
61. Mottron L, Burack JA, Iarocci G, Belleville S, Enns JT. Locally
oriented perception with intact global processing among adoles-
cents with high-functioning autism: evidence from multiple
paradigms. J Child Psychol Psychiatry. 2003;44:904–13.
62. Pearl J, Mackenzie D. The book of why: the new science of cause
and effect. New York: Basic Books; 2018.
63. Szatmari P, Georgiades S, Duku E, Bennett TA, Bryson S,
Fombonne E, et al. Developmental trajectories of symptom
severity and adaptive functioning in an inception cohort of pre-
school children with autism spectrum disorder. JAMA Psychiatry.
2015;72:276–83.
64. Bora E, Aydın A, Saraç T, Kadak MT, Köse S. Heterogeneity of
subclinical autistic traits among parents of children with autism
spectrum disorder: identifying the broader autism phenotype with
a data-driven method. Autism Res. 2017;10:321–6.
65. Fombonne E. Epidemiological trends in rates of autism. Mol
Psychiatry. 2002;7:S4–6.
66. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C,
et al. Global prevalence of autism and other pervasive develop-
mental disorders. Autism Res. 2012;5:160–79.
67. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J,
Warren Z, et al. Prevalence of autism spectrum disorder among
children aged 8 Years - autism and developmental disabilities
monitoring network, 11 Sites, United States, 2014. MMWR
Surveill Summ. 2018;67:1–23.